rs1052555

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000400.4(ERCC2):c.2133C>T(p.Asp711Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,738 control chromosomes in the GnomAD database, including 80,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6022 hom., cov: 32)

Exomes 𝑓: 0.31 ( 74695 hom. )

Consequence

ERCC2
NM_000400.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.818

Publications

79 publications found

Variant links:

Genes affected

ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ERCC2 Gene-Disease associations (from GenCC):

cerebrooculofacioskeletal syndrome 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
trichothiodystrophy 1, photosensitive
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
xeroderma pigmentosum group D
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P
sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
trichothiodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
xeroderma pigmentosum-Cockayne syndrome complex
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ERCC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 19-45352266-G-A is Benign according to our data. Variant chr19-45352266-G-A is described in ClinVar as Benign. ClinVar VariationId is 256018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.818 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERCC2	NM_000400.4 link	c.2133C>T	p.Asp711Asp	synonymous_variant	Exon 22 of 23	ENST00000391945.10	NP_000391.1	P18074-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERCC2	ENST00000391945.10 link	c.2133C>T	p.Asp711Asp	synonymous_variant	Exon 22 of 23	1	NM_000400.4	ENSP00000375809.4		P18074-1

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38856

AN:

152004

Hom.:

6024

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.360

Gnomad EAS

AF:

0.0612

Gnomad SAS

AF:

0.326

Gnomad FIN

AF:

0.396

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.334

Gnomad OTH

AF:

0.266

GnomAD2 exomes

AF:

0.282

AC:

70750

AN:

251206

AF XY:

0.295

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.381

Gnomad EAS exome

AF:

0.0651

Gnomad FIN exome

AF:

0.385

Gnomad NFE exome

AF:

0.338

Gnomad OTH exome

AF:

0.312

GnomAD4 exome

AF:

0.312

AC:

455390

AN:

1461616

Hom.:

74695

Cov.:

AF XY:

0.314

AC XY:

228392

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.102

AC:

3406

AN:

33478

American (AMR)

AF:

0.159

AC:

7132

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

9786

AN:

26132

East Asian (EAS)

AF:

0.0433

AC:

1719

AN:

39700

South Asian (SAS)

AF:

0.337

AC:

29057

AN:

86252

European-Finnish (FIN)

AF:

0.390

AC:

20786

AN:

53356

Middle Eastern (MID)

AF:

0.358

AC:

2059

AN:

5756

European-Non Finnish (NFE)

AF:

0.327

AC:

363442

AN:

1111844

Other (OTH)

AF:

0.298

AC:

18003

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

19839

39679

59518

79358

99197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11436

22872

34308

45744

57180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.255

AC:

38849

AN:

152122

Hom.:

6022

Cov.:

AF XY:

0.257

AC XY:

19127

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.111

AC:

4626

AN:

41498

American (AMR)

AF:

0.207

AC:

3162

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.360

AC:

1248

AN:

3468

East Asian (EAS)

AF:

0.0607

AC:

315

AN:

5188

South Asian (SAS)

AF:

0.328

AC:

1577

AN:

4814

European-Finnish (FIN)

AF:

0.396

AC:

4185

AN:

10576

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.334

AC:

22711

AN:

67970

Other (OTH)

AF:

0.262

AC:

553

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1403

2807

4210

5614

7017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

400

800

1200

1600

2000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.303

Hom.:

19989

Bravo

AF:

0.230

Asia WGS

AF:

0.160

AC:

561

AN:

3478

EpiCase

AF:

0.344

EpiControl

AF:

0.344

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with reduced cancer risk -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15834925) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Xeroderma pigmentosum, group D

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebrooculofacioskeletal syndrome 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Trichothiodystrophy 1, photosensitive

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.34

(source)

DANN

Benign

0.85

PhyloP100

-0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over